title: Calmodulin-dependent protein kinase II/cAMP response element-binding protein/Wnt/β-catenin signaling cascade regulates angiotensin II-induced podocyte injury and albuminuria.
abstract: Angiotensin II (Ang II) plays a pivotal role in promoting podocyte dysfunction and albuminuria, however, the underlying mechanisms have not been fully delineated. In this study, we found that Ang II induced Wnt1 expression and β-catenin nuclear translocation in cultured mouse podocytes. Blocking Wnt signaling with Dickkopf-1 (Dkk1) or β-catenin siRNA attenuated Ang II-induced podocyte injury. Ang II could also induce the phosphorylation of calmodulin-dependent protein kinase (CaMK) II and cAMP response element-binding protein (CREB) in cultured podocytes. Blockade of this pathway with CK59 or CREB siRNA could significantly inhibit Ang II-induced Wnt/β-catenin signaling and podocyte injury. In in vivo studies, administration of Ang II promoted Wnt/β-catenin signaling, aggregated podocyte damage, and albuminuria in mice. CK59 could remarkably ameliorate Ang II-induced podocyte injury and albuminuria. Furthermore, ectopic expression of exogenous Dkk1 also attenuated Ang II-induced podocytopathy in mice. Taken together, this study demonstrates that the CaMK II/CREB/Wnt/β-catenin signaling cascade plays an important role in regulating Ang II-induced podocytopathy. Targeting this signaling pathway may offer renal protection against the development of proteinuric kidney diseases.
authors.affiliation: Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, 262 North Zhongshan Road, Nanjing, Jiangsu 210003, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Jiang
authors.forename: Lingling
authors.initials: L
authors.lastname: Xu
authors.forename: Yuxian
authors.initials: Y
authors.lastname: Song
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Li
authors.forename: Junhua
authors.initials: J
authors.lastname: Mao
authors.forename: Allan Zijian
authors.initials: AZ
authors.lastname: Zhao
authors.forename: Weichun
authors.initials: W
authors.lastname: He
authors.forename: Junwei
authors.initials: J
authors.lastname: Yang
authors.forename: Chunsun
authors.initials: C
authors.lastname: Dai
mesh_terms: D000419:Albuminuria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000804:Angiotensin II / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D002461:Cell Line, Transformed; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D005260:Female; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007701:Kinetin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C516978:CK59 compound; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D051176:beta Catenin; D000804:Angiotensin II; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D007701:Kinetin
keywords: Angiotensin II; Calcium-calmodulin-dependent Protein Kinase (CaMK); Podocytes; Wnt Signaling; β-Catenin